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Tuberculosis 92 (2012) 377e383

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Tuberculosis

journal homepage: http : / / int l .e lsevierhealth.com/journals / tube

REVIEW

Diagnosis and therapy of tuberculous meningitis in children

Nicola Principi*, Susanna EspositoDepartment of Maternal and Pediatric Sciences, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,Via Commenda 9, 20122 Milan, Italy

a r t i c l e i n f o

Article history:Received 31 March 2012Received in revised form22 May 2012Accepted 29 May 2012

Keywords:ChildrenMeningitisMycobacterium tuberculosisTuberculosisTuberculous meningitis

* Corresponding author. Tel.: þ39 02 55032203; faE-mail address: nicola.principi@unimi.it (N. Princi

1472-9792/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.tube.2012.05.011

s u m m a r y

Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to theirrelative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devas-tating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors haveneurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis andprompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, thebest and most rapid way to confirm the diagnosis is controversial; the optimal choice, dose, and treat-ment duration of anti-tuberculosis drugs are not precisely defined, and the actual importance ofadjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This reviewis an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offerthe best solution to address this dramatic disease. In conclusion, we stress that new studies in childrenare urgently needed because data in the early years of life are more debatable than those collected inadults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude todiagnosis and therapy is necessary, because TBM is a devastating disease.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Tuberculous meningitis (TBM) occurs mainly in developingcountries where tuberculosis (TB) is more common and the widerincidence of the human immunodeficiency virus (HIV) favors theonset of a great number of cases. However, TBM is also encounteredin industrialized countries, particularly in recent years, as a conse-quence of the large immigration of infected people1 and thefrequent use of biological agents that favor TB development.2,3

Children are among the subjects who most frequently suffer fromTBM due to their relative inability to contain primary Mycobacte-rium tuberculosis infection in the lung.1,3 TBM is a devastatingdisease with about 30% mortality in the most severe forms;moreover, 50% of survivors have neurological sequelae despiteapparently adequate administration of antibiotics.4,5 Early diag-nosis and prompt treatment are crucial for reducing the risk ofa negative evolution. However, especially in children, the best andmost rapid way to diagnose the disease is controversial; theoptimal choice, dose, and treatment duration of anti-tuberculosisdrugs are not precisely defined, and the actual importance ofadjunctive therapies with steroids and neurosurgery have not beenadequately demonstrated. Consequently, the approach to pediatricTBM is frequently inadequate. This review is aimed at discussing

x: þ39 02 50320206.pi).

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present knowledge on the diagnosis and treatment of pediatricTBM in order to offer the best solution to address this dramaticdisease.

2. Diagnosis

Although early and rapid identification of TBM is crucial forsuccessful disease management, in most of the cases, diagnosis issignificantly delayed. Initial signs and symptoms of disease arenon-specific and the suspicion of TBMusually arises only some daysor weeks after the disease’s onset and is not different in childrenwho have or have not been vaccinated with Bacille Calmette-Gue-rin.6 Fever, headache, anorexia, and vomiting characterize theprodrome of disease in older children, whereas failure to thrive,poor appetite, vomiting, and sleep disturbances are more commonin younger ones.7 TBM is more easily suspected when thesesymptoms are associated with a history of recent contact witha case of documented TB or when, after the first days of disease,relevant neurological manifestations, such as cranial nerve palsy,occur.6,7

2.1. Probable or possible TBM

Diagnosis of probable or possible TBM requires signs andsymptomsofmeningitis in associationwith clinical, CSFandcerebralimaging findings suggestive of M. tuberculosis infection. The

N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383378

evidence of TB outside the CNS can further contribute to probable orpossible diagnosis. A score that includes the most common findingsin children with TBM and in which single findings are assigneda point according to the frequency with which they are usuallydemonstrated has been created by Marais et al.8 According to theseauthors, probable TBM is defined by a score between 10 and 12,whereas possible TBM is defined by a score higher than 6 (Table 1).

2.1.1. Clinical findingsThe low sensitivity and specificity of most of the relevant

neurologic symptoms has been largely demonstrated by severalclinical trials. Prodromal stage �7 days, optic atrophy on fundalexamination, focal deficit and abnormal movements were found tobe independently predictive of TBM (p< 0.007) in a group of chil-dren aged 1 months to 12 years,9 but optic atrophy is usually a lateoccurrence and abnormal movements are rare.

2.1.2. Laboratory findingsCSF modifications are common in children with TBM. In these

cases, CSF shows a clear appearance, moderate pleocytosis with

Table 1Diagnostic criteria for classification of definite, probable or possible tuberculousmeningitis.

Criteria

Clinical criteria Maximum categoryscore¼ 6

Symptom duration of more than 5 days 4Systemic symptoms suggestive of TB

(one or more of the following): weightloss or poor weight gain, night swabs orpersistent cough for more than 2 weeks

2

History of recent (within the past year)close contact with an individualwith pulmonary TB or a positivetuberculin skin test orinterferon-g release assay

2

Focal neurologic deficit (excludingfacial nerve palsies)

1

Cranial nerve palsy 1Altered consciousness 1

CSF criteria Maximum categoryscore¼ 4

Clear appearance 1Cells 10e500 per mL 1Lymphocytic predominance (>50%) 1Protein concentration >1 g/L 1CSF to plasma glucose ratio of less than

50% or an absolute CSF glucoseconcentration <2.2 mmol/L

1

Cerebral imaging criteria Maximum categoryscore¼ 6

Hydrocephalus 1Basal meningeal enhancement 2Tuberculoma 2Infarct 1Pre-contrast basal hyperdensity 2

Evidence of tuberculosis elsewhere Maximum categoryscore¼ 4

Chest X-ray suggestive of active TB:signs of TB¼ 2; miliary TB¼ 4

2/4

CT/MR/ultrasound evidence for TBoutside the CNS

2

M. tuberculosis cultured from another source(i.e., sputum, lymph node, gastric lavage,urine, blood culture)

4

Positive commercial M. tuberculosis NAATfrom extra-neural specimen

4

CNS, central nervous system; CT, computed tomography; MR, magnetic resonance;NAAT, nucleic acid amplification test; TB, tuberculosis.From Marais et al.,8 modified.

a predominance of lymphocytes, an increase in protein content anda very low glucose concentration. These findings are different fromthose usually reported for typical bacterial meningitis in which CSFis opaque, pleocytosis is very high, and neutrophils are predomi-nant. Reduction in glucose content is usually less marked incomparison to purulent bacterial meningitis, where CSF glucosevalues below 5 mg/dL will often be found. Clear appearance, whiteblood cell count between 50 and 500 per mL with 50% or morelymphocytes, protein content greater than 1 g/L and a glucosecontent less than 2.2 mmol/L are considered to be indicative ofTBM. However, atypical CSF findings have been repeatedlydescribed in children with TBM.7

To improve diagnosis of probable or possible TBM, other CSFtests have been recently studied. Among them, the evaluation ofadenosine deaminase activity (ADA), the measurement ofinterferon-gamma (IFN-g) release by lymphocytes, the detection ofM. tuberculosis antigens and antibodies, and the immunocyto-chemical staining of mycobacterial antigens (ISMA) in the cyto-plasm of CSF macrophages are those for which the greatest amountof data is available. However, none of these seems to have elevatedsensitivity and specificity, although they can be useful in somecases to support the diagnosis.

The ADA activity test is a rapid test that represents the prolif-eration and differentiation of lymphocytes as a result of the acti-vation of cell-mediated immunity afterM. tuberculosis infection.10,11

It has given good results in the diagnosis of the pleural, peritonealand pericardial forms of tuberculosis. When applied to patientswith TBM, it was found that ADA activity could not distinguishbetween TBM and other types of bacterial meningitis, but that itcould add useful information to suggest TBM once meningitis dueto different pathogens has been ruled out. ADAvalues from 1 to 4 U/L (sensitivity >93% and specificity <80%) can help to exclude TBMand values >8 U/L (sensitivity <59% and specificity >96%) canimprove the diagnosis of TBM (p< 0.001). However, valuesbetween 4 and 8 U/L are insufficient to confirm or exclude thediagnosis of TBM (p¼ 0.07).10 Moreover, false positive results canbe found in HIV-infected patients.11

Measurement of IFN-g release by lymphocytes stimulated byM. tuberculosis antigens has been demonstrated to be more accu-rate than skin testing for the diagnosis of latent TB and to be usefulin the diagnosis of extrapulmonary TB. However, sensitivity andspecificity of the test varied markedly according to the diseasesite.12When adapted toTBM, collected data vary sharply from studyto study. Liao et al. found that the test was 100% sensitive and 100%specific,12 whereas other authors reported a very poor value of thetest in diagnosing TBM.13 It has been suggested that the failure ofthe test in some studies could be ascribed to the fact thatlymphocytes die rapidly when stimulated with M. tuberculosisantigens ex vivo so that the test can be negative even if TBM isactually present.14

Detection of various M. tuberculosis antigen markers, such aslipoarabinomannan, purified protein derivatives, heat shockprotein of 62Kd and 14Kd, GroE, Ag 85 complex and 38Kd antigen,have been tried to confirm TBM diagnosis.15e17 However, theirpresence remains questionable and many of these antigens arereported in blood only, but not in the CSF and this questions theirveracity for the diagnosis of TBM. The same seems true for specificantibody detection.18

Use of ISMA in the cytoplasm of CSF macrophages is based onthe assumption that, during the initial stage of infection, ingestionof the bacilli by macrophages takes place and that during thesecond stage bacilli grow logarithmically within newly recruitedmacrophages.19 Consequently, the positivity of the test indicatesthat viableM. tuberculosis isolates are present in CSF. A recent studyin which this test was evaluated in 393 patients, among whom

N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 379

some with definite TBM, has demonstrated that it has a sensitivityof 73.5% and specificity of 90.7% with positive and negativepredictive values of 52.9% and 96.0% respectively.20 This means thatthis test can be useful, in actual fact, to exclude TBM, but that itssensitivity is too low to diagnose definite TBM.

2.1.3. ImagingSimilarly to clinical and laboratory findings, cerebral imaging

can also contribute to diagnosing probable or possible TBM.However, discrimination between TBM and another cerebraldisease is frequently very difficult. The most common braincomputed tomography (CT) or magnetic resonance (MR) features inchildren with TBM are hydrocephalus, which can be demonstratedin about 80% of cases,21 and basal meningeal enhancement, foundin 75% of young patients.22 Infarction, as a result of ongoingvasculitis, particularly of the basal ganglia and of the areas of themedial striates and thalamoperforating arteries, and tuberculomacan be found in a smaller number of TBM pediatric cases.23,24 MRhas a higher sensitivity than CT in the identification of CNS modi-fication, although it does not seem to offer more help in dis-tinguishing TBM from other CNS diseases such as viral encephalitis,cryptococcal meningitis or cerebral lymphomas that can havesimilar cerebral imaging.25 However, a combination of basalmeningeal enhancement, infarction and hydrocephalus was foundto have a high specificity for the diagnosis of TBM, whereas basalmeningeal enhancement was reported as the most sensitivefeature.22 Recently, it was reported that border zone necrosis (BZN)of the brain parenchyma in areas adjacent to meningeal inflam-mation can occur in 50% of children with TBM.26 Detection andconfirmation of cytotoxic edema associated with BZN usingdiffusion-weighted MR can offer further support to probable orpossible TBM diagnosis. However, it has to be highlighted that instage 1 TBM imaging findings may be normal, yet it is at that stagethat treatment should be started in order to prevent brain damage.

2.2. Evidence of TB outside the CNS

The evidence of TB infection or disease outside the CNS cansignificantly increase the probability or possibility that a child withcerebral signs and symptoms can have TBM. However, a greatnumber of patients, especially when HIV negative, will presentwith normal chest radiography or negative tuberculin skintesting.27 Moreover, particularly in high TB prevalence areas,a positive skin test with an unrelated illness has been frequentlydocumented. Taking samples from sites of frequent TB infectionsuch as lymph nodes, lung and gastric fluid can increase the like-lihood of a positive culture. Gastric aspirationwas positive in 68% ofchildren with TBM.28

In conclusion, considering the need for a rapid diagnosis of TBM,all possible efforts to demonstrate the probable or possible pres-ence of this disease must be pursued using all available laboratorytests and imaging techniques. Moreover, the potential severity ofTBM calls for the immediate treatment of all the doubtful cases.

2.3. Confirmed diagnosis of TBM

Independently from the characteristics and duration of theprodromal stage, a definite diagnosis of TBM can be made onlywhen, after a lumbar puncture (LP) in a patient with signs andsymptoms of central nervous system (CNS) disease, acid-fast bacilli(AFB) are seen and/or M. tuberculosis is detected by molecularmethods and/or cultured in cerebrospinal fluid (CSF). The sameconclusion can be drawn from autopsy when M. tuberculosis isidentified in histological lesions of the CNS. This is in linewith whathas been defined by most of the authors who have made the

attempt to standardize clinical case definition of TBM for use inclinical research.5, 29e34

However, all the methods for the confirmation of the diagnosisof TBM risk further delay in diagnosis and initiation of therapy.35e37

Culture requires >2e3 weeks to give results. Moreover, bothmicroscopic AFB detection and culture isolation have low sensi-tivity, particularly in children in whom these allow for identifica-tion of only about 20% of cases. Finally, modern molecular methodscan have, at the same time, both low sensitivity and low specificity.Sensitivity of traditional microbiological tests seems to be strictlydependent on the amount of CSF that is sampled, the frequency ofLPs, the time devoted to the microscopic search for the organism,and the moment in which the CSF is drawn. The minimum volumeof CSF to obtain reliable results seems to be 6 mL,35 an amountdifficult to be safely obtained in younger children that have a lowtotal volume of CSF.36 In comparison with a single LP, four LPs canincrease sensitivity of microscopy examination and culture from37% and 52% to 87% and 83%, respectively.37 However, in pediatricsseveral lumbar punctures are not easily performed, mainly becauseof the aversion of parents to let their children undergo repeatedinvasive procedures. Thirty minutes are considered the minimumtime needed for a correct evaluation of CSF by microscopy36 and ina busy laboratory this may not be possible. Finally, antibioticadministration rapidly reduces the number of pathogens in the CSF.Anti-tuberculosis drugs are usually started immediately after TBMis suspected and consequently LPs are negative even in childrenactually suffering from the disease.

Accuracy of nucleic acid-based amplification (NAA) tests,though better than that of conventional microscopic methods,38

was not considered completely satisfactory for many yearsbecause their sensitivity and specificity in identifyingM. tuberculosis, in comparisonwith culture, ranged from 2% to 100%and from 75% to 100%, respectively.39 The most important reasonfor the low sensitivity of some of the first polymerase chain reac-tion (PCR)-based methods was the use of a single target foramplification. Most studies have used the IS6110 gene ofM. tuberculosis that is usually present in multiple copies in thebacterial genome assuring high sensitivity. Unfortunately, this geneis absent in a significant number of isolates, so that a false negativeresult was regularly found when patients infected by these isolateswere studied.40,41 More reliable results have been obtained in morerecent years when amplification of multiple gene targets from CSFsamples was performed. Kusum et al. evaluated a multiplex PCRusing protein b, MPB64 and IS6110 primers and found that thismethod had a sensitivity of 94.4% and a specificity of 100% inculture-confirmed cases.42 Recently, molecular methods capable ofsimultaneously identifying both M. tuberculosis and resistance ofthe strain to antibiotics have been developed. Among these, theXpert M. tuberculosis/RIF assay seems to be the most promising,although no data regarding its use in extrapulmonary TB areavailable.43 Finally, preliminary studies have suggested thatmolecular methods could be used to quantify the bacterial load inCSF and consequently to evaluate treatment response.44

In conclusion, making a definite diagnosis of TBM is stilla problem. In many cases, diagnosis remains probable or possibleand treatment is initiated without the demonstration of the pres-ence of M. tuberculosis in CSF.

3. Treatment

Treatment of TBM is based on three different components:administration of anti-infective drugs active againstM. tuberculosis,modulation of the destructive elements of the immune response,and management of increased intracranial pressure.

Table 3Recommended daily dosages of second-line anti-tuberculous drugs for treatment oftuberculous meningitis in infants and children.

Drug Dosage

Ethionamide 20 mg/kg/24 h (max 1 g/day) orally as asingle daily dose

Cycloserine 10e15 mg/kg/24 h (max 1 g/day) orallyas a single daily dose

Steptomycin 20e40 mg/kg/24 h (max 1 g/day) i.m.or i.v. as a single daily dose

Para-amino-salicylic acid 200e300 mg/kg/24 h orally in 2e4 dosesCapreomycin 15e30 mg/kg/24 h (max 1000 mg) orally

as a single daily doseAmikacin and Kanamycin 15e30 mg/kg/24 h (max 1 g/day) i.m.

or i.v. as a single daily doseOfloxacin 15e20 mg/kg/24 h (max 800 mg) orally

as a single daily doseLevofloxacin 7.5e10 mg/kg/24 h (max 500 mg) orally

as a single daily doseMoxifloxacin 7.5e10 mg/kg/24 h (max 500 mg) orally

as a single daily doseCiprofloxacin 20e30 mg/kg/24 h (max 1.5 g) orally

as a single daily dose

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3.1. Anti-infective therapy

Contrary to what applies to pulmonary tuberculosis, recom-mendations for anti-infective therapy in TBM are, in general, notbased on well-conducted clinical trials. Few data, particularly inchildren, are available to guide the clinician who derives theschemes for treatment of TBM from those used for pulmonary TB.This explains why most experts recommend that the treatment ofTBM follows the model of short-course chemotherapy with anintensive phase of treatment with several drugs followed bya continuation phase in which only two drugs areadministered.45,46

Table 2 summarizes the main guidelines for treatment of pedi-atric TBM and Table 3 shows second-line drugs that could be usedin case of resistant strains taking in account that very few data oftheir real efficacy, safety and tolerability in children are available.Before the emergence of multidrug-resistant M. tuberculosis, threedrugs were considered adequate for the first phase. More recently,in order to address the problem of resistance, four antibiotics forthe initial months of treatment are preferred. However, there is noagreement on the duration of each of the two phases and on thetotal length of therapy. The intensive phase can range from 2 to 6months and total treatment from 6 months to one year.47 Unfor-tunately, studies comparing the different schemes of antibioticadministration in children are not available.48,49 Studies regardingthe outcome of 6-month regimens have demonstrated that therelapse ratewas not significantly different from that reported whenlonger periods of antibiotic administrationwere used.48 This seemsto speak in favor of the shortest therapy. However, because most ofthese data have been collected in adults, no definitive conclusionscan be drawn when children with TBM have to be treated.According to Donald, in situations where the directly observedtreatment and follow-up after treatment completion is impeccable,a 6-month treatment duration is probably satisfactory.47 Whentreatment supervision and/or follow-up are questionable, it may bebetter practice to prolong length of treatment.47

For several years now, the drugs considered essential by theWorld Health Organization (WHO) to treat pulmonary TB in chil-dren are isoniazid (INH), rifampicin (RMP),pyrazinamide (PZA), andethambutol (EMB).50 Other drugs, such as streptomycin (SM) orother aminoglycosides, ethionamide (ETH) and cycloserine are

Table 2Main guidelines for the treatment of tuberculous meningitis in infants and children.

British Infection SocietyIsoniazid 10e20 mg/kg/24 h (max 500 mg) orally for 12 monthsRifampin 10e20 mg/kg/24 h (max 600 mg) orally for 12 monthsPyrazinamide 30e35 mg/kg/24 h (max 2 g) orally for 2 monthsEthambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 monthsPrednisolone 4 mg/kg/24 h orally for 4 weeks, followed by a

reducing course over 4 weeks

American Thoracic Society, CDC, and Infectious Diseases Society of AmericaIsoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 9e12 monthsRifampin 10e20 mg/kg/24 h (max 600 mg) orally for 9e12 monthsPyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 monthsEthambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 monthsDexamethasone 8 mg/day/24 h orally for children weighing less than 25 kg

and 12 mg/day for children weighing 25 kg or more for 3 weeks,followed by a reducing course over 3 weeks

World Health OrganizationIsoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 6 monthsRifampin 10e20 mg/kg/24 h (max 600 mg) orally for 6 monthsPyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 monthsStreptomycin 20e40 mg/kg (max 1 g) i.m. or i.v. for 2 monthsPrednisone 2 mg/kg/24 h orally for 4 weeks, followed by a

reducing course over 1e2 weeks

considered second-line drugs because of their toxicity.50 However,when TBM has to be treated ETH and cycloserine that havea reasonable CSF penetration, even better of that of EBM can beconsidered where they are available.51,52 Newer anti-tuberculosisdrugs, such as fluoroquinolones, have been scarcely used in pedi-atric TBM and are off-label in children, although for both penetra-tion in CSF and in-vitro efficacy against M. tuberculosis, they areconsidered promising therapeutic options.50

Independently from the drugs prescribed, the scheme of admin-istrationused, and the total durationof therapy, INH remains thedrugmost widely prescribed in children for initial TBM treatment.50 Thechoice of INH is based on several positive factors: the good absorptionby the gastrointestinal tract, the rapid diffusion in body compart-ments including CSF and the low toxicity. Moreover, it rapidly killsmost of the replicating M. tuberculosis and, consequently, protectscompanion drugs against the development of resistance, reduces therisk of infecting contacts and leads to a more rapid mitigation ofdisease symptoms. In children, INH is recommended at the dose of10 mg/kg/day (range:6e15 mg/kg/day,maximum500 mg), generallyuseful to reach in CSF concentrations that are high enough to elimi-nate fully sensitive M. tuberculosis or resistant mutants with a rela-tively low minimum inhibitory concentration (MIC) even in patientswho are fast acetylators.53,54 When M. tuberculosis resistance is sus-pected or demonstrated, the highest doses have to be administered,striking the right balance between toxicity and optimal efficacy.

RMP has the advantage of killing low or non-replicatingM. tuberculosis, thus complementing INH activity and allowingthe sterilization of lesions. Unfortunately, it has several limitsbecause its concentrations in CSF do not exceed 10% of those inplasma,55 its absorption is negatively influenced by food andantacids56 and it has a relevant protein binding action that cansignificantly reduce its clinical efficacy.57 RMP is officially recom-mended at the dose of 10e20 mg/kg/day45,46 but, considering theMIC of susceptible M. tuberculosis and the concentrations reachedin CSF of children,58 it has been recommended to administer thehighest dosage in young children and infants <10 kg and at least15 mg/kg/day in older patients weighing between 10 and 20 kg.47

The dose of 10 mg/kg/day could lead to CSF levels <1.0 mg/mL,which is ineffective against most M. tuberculosis, particularly whenstrains with increased MIC are present. However, raising the dosehas no effect on highly resistantmutants as their MIC is far too high.

For the early phase of therapy, PZA and any of the second-linedrugs are usually administered. PZA has a good penetration inCSF and, despite a very low early bactericidal activity in the first

N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 381

days of treatment, it is important because in the course of time itbecomes as effective as INH and RMP.59,60 Moreover, together withRMP, it makes an essential contribution to the sterilization oflesions and has an important role in reducing the risk of recur-rence.61 PZA is recommended at the dose of 30e35 mg/kg/dailywith the highest dosage for younger children.With these regimens,CSF concentration in excess of 20 mg/mL higher than the MIC of PZAis reached in most children.62

The fourth drug to complete the antibiotic regimen in the earlyphase of TBM therapy is usually chosen from EMB or SM. Both havelimited CSF penetration, low bactericidal activity and do notcontribute to the sterilization of lesions and reduction of the risk ofrelapse. Their contribution to the treatment of TBM is probablyminor, although they protect companion drugs against the emer-gence of resistance.47

The growing emergence of resistant strains has raised thequestion of the importance of resistance to TBM outcome. Availabledata clearly indicate that resistance to both INH and RMP signifi-cantly worsen the final outcome.45 The effect of resistance toa single drug is more controversial. Regarding INH, some studiesindicate that INH resistance does not influence TBM outcome,63,64

whereas other studies seem to associate INH resistance to a signif-icant higher risk of death.65 These different findings may be due todifferent doses of INH used and different resistant mutants.However, in order to minimize risks, it has been suggested thatduration of treatment for TBM caused by INH-resistant organismsshould be extended and always include PZA as well as a new anti-M. tuberculosis antibiotic.47

3.2. Adjunctive steroids

In meningitis, most of the damage derives from the immuneresponse elicited by the presence of bacterial pathogens in theCNS.66 This leads to a very relevant inflammatory process withsignificant infiltrative, proliferative and necrotizing vessel pathol-ogies.67 Anti-tuberculous chemotherapy and the administration ofthalidomide and salicylates appear to be relatively ineffective inpreventing vascular complications that remain the major unre-solved problem related to TBM. Corticosteroids have been used inTBM for over 50 years, although the real importance of these drugsin this disease is not completely defined. A meta-analysis recentlycarried out that comprised 7 randomized controlled trials involvinga total number of 1140 participants, both children and adults, hasdemonstrated that in HIV-negative subjects prednisolone ordexamethasone significantly reduced the risk of death (relative risk[RR], 0.78; 95% confidence interval [CI], 0.67e0.91) or disablingresidual neurological deficit (RR 0.82; 95% CI, 0.70e0.97) with mildand treatable adverse events.68 On the contrary, no effect wasreported in HIV-infected patients. The positive effect on HIV-negative subjects was found independently from the severity ofthe disease, thus suggesting that this therapy should be added toanti-infective therapy in all children with TBM.69,70

The best steroid and the most effective scheme of administra-tion are not known because no data comparing different regimensare available at the moment. Moreover data collected in childrenare few. According to the suggestions of some American andEuropean Scientific Societies,45,46 it could be suggested the use oforal compounds for 3 or 4 weeks with subsequent reduction in fewdays.

3.3. Management of increased intracranial pressure

Hydrocephalus is common in children with TBM. Its manage-ment is debated. Diuretics, repeated LPs or CSF diversion throughventriculoperitoneal or atrial shunting can be used, according to

the severity of increased intracranial pressure.71e74 Shunting ispreferred by most experts when hydrocephalus is non-communicating or when medical treatment fails even if it is notknown which kind of shunting is the best.74 In communicatinghydrocephalus, diuretics are generally effective in reducing the riskof long-term neurologic impairment. Endoscopic third ven-triculostomy is considered a possible option, particularly in patientswho have experienced multiple episodes of shunt dysfunction.75

4. Conclusions

Despite undeniable advances in the identification of markers ofdefinite, probable or possible TBM have been made in recent years,most of the problems that pediatricians and neurologists have toface in TBM are still unsolved. Themost important difficulty regardsearly diagnosis because in those patients in whom TBM is sus-pected early enough present treatment is sufficient to bring aboutcomplete cure in the majority of cases, at least when pathogens arefully drug susceptible and treatment is complied with. More diffi-culties in achieving cure can arise when treatment is delayed andwhenmultidrug-resistant pathogens are the cause of the disease. Inthis case prognosis is poor, particularly in children because it is notdefinitively clear what has to be done when resistance ofM. tuberculosis to one ormore antibiotics is present, which durationof treatment is to be recommended and what is the actual role ofadjunctive therapy. New studies in children are urgently needed. Inthe meantime, when treating a child with suspected TBM, the mostaggressive attitude is to be used both for diagnosis and for therapy,because TBM is an extremely devastating disease.

Funding: This study was supported by a grant from the ItalianMinistry of Health (Bando Giovani Ricercatori 2007).

Competing interests: The authors have no conflict of interestto declare.

Ethical approval: This review was approved by the EthicalCommittee of Fondazione IRCCS Ca’ Granda Ospedale MaggiorePoliclinico, Milan, Italy and all the papers included in this reviewhave been approved by local Ethical Committees.

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